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Item Open Access The development and validation of quantitative methods for the determination of stavudine and alfuzosin in plasma and monic acid in urine(University of the Free State, 2003-05) Wiesner, Joachim Lubbe; Swart, K. J.; Hundt, H. K. L.English: The development and validation of bio-analytica) assay methods suitable for the quantification of stavudine in plasma, alfuzosin in plasma and monic acid in urine is discussed. A short summary of these methods are given: • A sensitive method for the determination of stavudine in plasma was developed, using highperformance liquid chromatographic separation with tandem mass spectrometric detection. The samples were extracted from plasma with Waters, Sep-Pak®Vac, 100 mg, tC18®solid phase extraction (SPE) columns. Chromatography was performed on a Supelco Discovery" C18, 5 urn, 150 x 2 mm column with a mobile phase consisting of ammonium acetate (0.01 M): acetonitrile: methanol (800:100:100, v/v/v) at a flow rate of 0.3 ml/min. Detection was achieved by an Applied Biosystems API 2000 mass spectrometer (LC-MS/MS) set at unit resolution in the multiple reaction monitoring mode (MRM). Atmospheric pressure chemical ionization (APCl) was used to obtain deprotonated ions (molecular ion m/z 223.1 to the product ion m/z 42.01). The mean recovery for stavudine was 94 % with a lower limit of quantification set at 4 ng/ml. This assay method makes use of the increased sensitivity and selectivity of mass spectrometric (MS/MS) detection to allow for a more rapid (extraction and chromatography) and selective method for the determination of stavudine in human plasma than has previously been published. The assay metod was used to quantitatively determine stavudine concentrations in plasma samples to follow the concentration vs. time profile for at least five half lives of the drug after a single 40 mg oral dose of stavudine was given to healthy adult male human subjects. • A selective, sensitive and rapid liquid chromatography-tandem mass speetrometry method for the determination of alfuzosin in plasma was developed. An Applied Biosystems API 2000 triple quadrupole mass speetrometer in multiple reaction monitoring (MRM) mode, using TurboIonSpray (TIS) with positive ionisation was used (molecular ion of alfuzosin m/z 390.2 to the product ion m/z 71.2; molecular ion of prazosin m/z 384.2 to the product ion m/z 95.0). Using prazosin as an internal standard, liquid-liquid extraction was followed by CI8 reversed phase liquid chromatography and tandem mass spectrometry. The mean recovery for alfuzosin was 82.9 % with a lower limit of quantification set at 0.298 ng/ml, the calibration range being between 0.298 and 38.1 ng/ml. This assay method makes use of the increased sensitivity and selectivity of tandem mass spectrometric (MS/MS) detection to allow for a more rapid (extraction and chromatography) and selective method for the determination of alfuzosin in human plasma than has previously been published. The assay method was used to quantify alfuzosin in human plasma samples generated in a multiple-dose (5 mg bd.) study at steady state. • Two selective methods for the determination of monic acid (a metabolite of mupirocin) in urine were developed, using high-performance liquid chromatographic separation with tandem mass spectrometric detection. An Applied Biosystems API 2000 triple quadrupole mass spetrometer in multiple reaction monitoring (MRM) mode, using TurboIonSpray (TIS) with positive ionisation, was used (molecular ion of monic acid m/z 345.2 to the product ion m/z 327.0) The minimal sample preparation and short chromatography time (retention time ~ 3.8 min.) makes these methods suitable for the assay of large numbers of samples per day. Linearity (weighted 1/concentratiorr²) was established from 50.1 to 1001 ng/ml for the direct injection method, and linearity (weighted 1/concentration) was established from 15.8 to 1013 ng/ml for the SPE method. The assay method was used for the determination of monic acid concentrations in human urine in order to detect and quantify the absorption of mupirocin after multiple topical applications ofO.5 g of a 2 % ointment. Analytical data that were generated during these three research projects are discussed in this dissertation, improvements and novelties to existing methods are elucidated. The methods for the determination of stavudine and alfuzosin have been published. Both full-length publications are included in this dissertation, together with correspondence between myself and the journal editors and referees. The assay methods for monic acid will soon be submitted for publication in the Journal of Chromatography B.Item Open Access Factors influencing antibiotic use in the paediatric intensive care unit at Universitas Hospital from 1998 to 2007(University of the Free State, 2013-02) Van Wyk, Riana; Walubo, A.English: Many antibiotics have been developed and are available on the market. An increase in the use of antibiotics in hospitals was observed and antibiotics are among the medicines most commonly prescribed to paediatric patients. Resistance to antibiotics is increasing and is a major problem not only in the Paediatric Intensive Care Unit at Universitas Hospital in Bloemfontein, but in South Africa in general. The continued value and effectiveness of antibiotics depend on careful use to avoid bacterial resistance from developing. Thus, guidelines for rational antibiotic use and prevention of resistance should be developed and implemented. This requires an understanding of the factors influencing antibiotic use in a particular setting, in this case the Paediatric Intensive Care Unit at Universitas Hospital. Therefore, the aim of this study is to describe the factors that influence the use of antibiotics in the Paediatric Intensive Care Unit from 1998 to 2007. This research consisted of a retrospective study of the records of patients admitted to the Paediatric Intensive Care Unit from 1998 to 2007. Using a datasheet, the following information was captured and evaluated: patients’ demography, indication for admission, co-morbid conditions, antibiotic and other drug therapy, culture and sensitivity and other relevant parameters. Of the 1 221 patients admitted during the study period, information could only be retrieved for 967 patients, and of these 685 patients (385 males and 299 females) met the study criteria. The Paediatric Intensive Care Unit performance, measured as Intensive Care Unit utilisation, was optimal at 63%, implying that no patient needing intensive care was denied. The most common conditions on admission were respiratory (23.4%), gastro-intestinal (22%) and cardiovascular (19%) related problems. Pneumonia (8.9%) was the most common infective condition. The most common infective complications while in the Paediatric Intensive Care Unit were pneumonia (35.6%), septicaemia (11.1%) and urinary tract infection (8.8%). Broad-spectrum antibiotics were prescribed the most widely. The top ten antibiotics included cefotaxime (18.2%), amikacin (14.7%), vancomycin (9.8%), cefuroxime (8.1%) imipenem (7.5%), metronidazole (7.2%), penicillin G (6.5%), cloxacillin (4.1%), co-trimoxazole (2.7%) and gentamicin (2.4%). The top ten bacteria genera cultured were Staphylococcus (29.3%), Klebsiella (11.9%), Acinetobacter (11.7%), Pseudomonas (11.2%), Escherichia (8.5%), Enterococcus (5.9%), Streptococcus (4.1%), Enterobacter (4.1%), Stenotrophomonas (3.4%) and Haemophilus (2%). There was high resistance of the Staphylococcus genus to penicillins and penicillin-allergy substitutes (>80%, with methicillin-resistance of 85%), but no resistance to vancomycin was observed. The Klebsiella and Pseudomonas genera exhibited considerable resistance to most aminoglycosides (40–78%) and cephalosporins (70–100%), but Klebsiella remained sensitive to imipenem (1.9%), while Pseudomonas was moderately sensitive to amikacin (22.9%). The nosocomial bacteria genera Acinetobacter and Stenotrophomonas were resistant (>70%) to almost all antibiotics excluding tobramycin (25.8%) for Acinetobacter and co-trimoxazole (10.5%) for Stenotrophomonas. Lastly, the persistently challenging factors that influenced antibiotic use in the Paediatric Intensive Care Unit from 1998 to 2007 were common bacteria cultured from specific specimens, bacterial innate resistance, interaction of bacterial and host factors (multiple and severe infections), disease pattern, new antibiotics, overuse of antibiotics, length of stay, personal preferences and treatment guidelines. In conclusion, it was illustrated that bacterial resistance to antibiotics is increasing, and that antibiotic use in the Paediatric Intensive Care Unit at Universitas Hospital was greatly influenced by the efforts to contain antibiotic resistance.